Preat et al. Diagnostic Pathology 2014, 9:26http://www.diagnosticpathology.org/content/9/1/26

RESEARCH Open Access

Differences in breast carcinomaimmunohistochemical subtypes betweenimmigrant Arab and European womenFanny Preat, Philippe Simon and Jean-Christophe Noel*

Abstract

Background: There is a dearth of information on the clinicopathological differences, including the molecularsubtypes, of breast carcinomas from immigrant Arab women in Europe. Therefore, the aim of our study was toexamine and compare these features in immigrant Arab/Moroccan patients with those of European women.

Methods: Included in this study were 441 cases of breast cancer: 91 Arab/Moroccan women and 350 Europeanwomen. Age, size, grade, node involvement, and immunohistochemical profile (classification into the followingsubtypes: luminal A, luminal B, HER2 +/ER -, and triple negative) were analyzed.

Results: The average age of breast cancer presentation in Arab women is almost a decade earlier than in Europeanwomen (49 versus 60 years old; p = 0.00001). Arab patients also had a higher average tumor size (25 mm versus19 mm; p =0,008) and more grade 3 and less grade 1 tumors (p = 0.02). It should be noted, however, that thisvariability in the size and grade do not appear statistically significant when compared in Arab and Europeanpatients under 50 years old. In contrast, independent of age, the immunohistochemical subtypes were differentbetween the two populations, with a greater number of luminal B subtype and fewer luminal A subtype (p <0.02)in Arab patients.

Conclusions: Arab patients with breast carcinoma have different clinicopathological features from Europeanpatients, mainly the age of cancer presentation. Their immunohistochemical profile is also different, with moreluminal B and less luminal A subtypes, suggesting that there are not only clinicopathological differences but alsodisparities in the expression profiling in these women.

Virtual slide: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2104813621113288.

Keywords: Arab, European, Breast carcinoma, Molecular classification, Luminal A, Luminal B, Immunohistochemistry

BackgroundIn Belgium, breast cancer accounts for almost 13% of allcancers and each year 9,400 new cases are observed. Itsincidence is estimated at 146/100,000 [1]. The origin ofthis cancer is likely multifactorial and many factors havebeen implicated, including the woman’s reproductivelifestyle, endogenous hormones, exogenous hormones,adiposity, physical activity, nutrition, alcohol consump-tion, smoking, environmental toxins, and genetic suscep-tibility in inherited syndromes [2]. Breast cancer rates

* Correspondence: Jean-Christophe.Noel@erasme.ulb.ac.beDepartment of Senology, Erasme University Hospital-ULB, Route de Lennik808, B-1070 Bruxelles, Belgium

© 2014 Preat et al.; licensee BioMed Central LtCommons Attribution License (http://creativecreproduction in any medium, provided the orwaiver (http://creativecommons.org/publicdomstated.

also differ by race and ethnicity [3]. It has been sugges-ted that breast cancer in Arab populations has specificmorphological and molecular characteristics, includingpoorly differentiated pathological features and increasedHER2 overexpression [4]. Naturally, Arab populationsare not homogeneous and have genetic diversity [5].However, in a recent publication El Fatemi et al. demon-strated that in a Moroccan Arab population, the luminalB subtype was the most prevalent [6]. These studies,however, were performed on the indigenous population,and there are no data on the Moroccan Arab immigrant

d. This is an Open Access article distributed under the terms of the Creativeommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andiginal work is properly cited. The Creative Commons Public Domain Dedicationain/zero/1.0/) applies to the data made available in this article, unless otherwise

Table 1 Clinicopathological characteristics of the breastcancer patients (all ages combined)

European Arabic/Moroccan P-value

Number 350 91

Mean age (SD) 60 (13) 49 (11) 0.00001

Mean size (SD) 19 (14) 25 (18) 0.008

pT

< 20 mm 216 (62%) 45 (49%) 0.04

≥ 20 mm 134 (38%) 46 (51%)

Tumor grade

G1 69 (20%) 7 (8%) 0.02

G2 169 (48%) 41 (45%) NS

G3 112 (32%) 43 (47%) 0.01

Nodes

N positive 78 (22%) 26 (29%) NS

N Negative 272 (78%) 65 (71%)

Estrogen receptors

Positive (>1%) 301 (86%) 72 (79%) NS

Negative 49 (14%) 19 (21%)

Progesterone receptors

Positive (>1%) 266 (76%) 58 (64%) 0.02

Negative 84 (24%) 33 (36%)

Mean Ki-67 (SD) 20 (14) 27 (20) 0.003

Molecular classification

Luminal A 160 (46%) 21 (23%) 0.001

Luminal B 141 (40%) 51 (56%) 0.02

HER2 17 (5%) 5 (6%) NS

Triple negative 32 (9%) 14 (15%) NS

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women in Western Europe. Since the Moroccan immi-grant population is the most common at our institution,the aim of this study was to define the morphologicaland immunohistochemical (surrogates to molecular clas-ses) characteristics of breast carcinomas in these immi-grant Moroccan Arab patients and compare them withthe European native population.

Materials and methodsBreast carcinoma specimens in formalin-fixed, paraffin-embedded tissue blocks from 441 female patients diag-nosed with invasive carcinoma from january 2008 todecember 2012 were retrieved from the archives of theDepartment of Pathology, Erasme University Hospital.This study was approved by the local ethics committee(Erasme University Hospital, reference number: 2013/027)and included 350 European white women and 91 MoroccanArab patients. The pathological stage and histologicalgrade were defined according to the criteria of the WorldHealth Organization 2012 [7]. The estrogen receptor (ER),progesterone receptor (PR), Ki-67 labeling index, andHER2 expression were evaluated at the time of the ori-ginal diagnosis by immunohistochemistry, as previouslydescribed [8-10]. A clinically positive test for the receptorsis defined as nuclear staining in ≥1% of the tumor cells[8]. HER2 immunoreactivity was performed using the Or-acle HER2 test (clone CB11; Leica Microsystems GmbH,Wetzlar, Germany) according to the manufacturer’s in-structions, as previously described [10]. The scoring wasassessed with the recommendations of the American So-ciety of Clinical Oncology [11]. All of the HER2 scores of2+ and 3+ were analyzed using the fluorescent in situhybridization (FISH) PathVysion HER2 DNA test (Abbottlaboratories, Abbott Park, USA) according to the manu-facturer’s instructions. Signal ratios (HER2/CEP17) of ≥2were classified as amplified. In this study, only 2+ and 3+tumors with a HER2 FISH amplification were consideredas a positive result. A subtype immunohistochemical clas-sification (surrogates to molecular classes) was adopted tocharacterize the tumors, using the following criteria:Luminal A, when either one or both of the ER and PR werepresent, HER2 was negative and Ki-67 <14%; Luminal B,when ER and/or PR were present and either Ki-67 ≥14% orHER2 was positive; HER2 positive, when ER and PR wereabsent and HER2 was positive irrespective of the Ki-67;and Triple negative, when ER and PR were absent andHER2 was negative. The correlation analysis was con-ducted using the χ2 test and Fisher’s exact probably test.For the comparison of the means, the student’s t-test wasused. Results were considered significant when p <0.05.

ResultsThe clinicopathological characteristics of the 441 pa-tients are summarized in the Table 1. Arab/Moroccan

patients were characterized by an average age of pre-sentation for breast cancer almost a decade earlier thanin European individuals (49 versus 60 years old; p =0.00001). In addition, the size of the tumor in these pa-tients was larger (25 mm versus 19 mm; p = 0.008), theincidence of grade 3 tumors more frequent (p = 0.01),the grade 1 less frequent (p = 0.02), the percentage of PRpositive lesions was less (p = 0.02), the mean Ki-67 indexwas higher (27% versus 20%; p = 0.003), the Luminal Atumor was less frequent (p = 0.001), and the Luminal Bwas more frequent (p = 0.02). To ensure these resultswere not biased by the age at the time of the presenta-tion of cancer, we only extracted premenopausal patientsfrom this series. This enabled us able to compare groupswith an almost identical age (43 versus 42 years old). In-terestingly, despite these adjustments, the Arab/Moroccanpatients continued to display less Luminal A tumors (p =0.01) and more Luminal B tumors (p = 0.02) (Table 2)(Figure 1).

Table 2 Clinicopathological characteristics in thepremenopausal women

European Arabic/Moroccan P-value

Number 86 56

Mean age (SD) 43 (4) 42 (15) NS

Mean size (SD) 22 (14) 24 (17) NS

pT

< 20 mm 47 (55%) 30 (54%) NS

≥ 20 mm 39 (45%) 26 (46%)

Tumor grade

G1 12 (14%) 1 (2%) 0.02

G2 42 (49%) 27 (48%) NS

G3 32 (37%) 28 (50%) NS

Nodes

N positive 23 (27%) 18 (32%) NS

N Negative 63 (73%) 38 (68%)

Estrogen receptors

Positive (>1%) 71 (83%) 45 (80%) NS

Negative 15 (17%) 11 (20%)

Progesterone receptors

Positive (>1%) 61 (71%) 37 (66%) NS

Negative 25 (29%) 19 (34%)

Mean Ki-67 (SD) 24 (18) 29 (20) 0.04

Molecular classification

Luminal A 35 (41%) 10 (18%) 0.01

Luminal B 36 (42%) 35 (63%) 0.02

HER2 4 (4%) 3 (5%) NS

Triple negative 11 (13%) 8 (14%) NS

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DiscussionThe study of possible ethnic differences in breast cancerhas mainly occurred in the United States [12]. Recently,new data have been described for Arab populations, butthe true prevalence of breast cancer remains uncertain

Figure 1 Immunohistochemical profile surrogates of the molecular cl

[4,13-17]. For the majority of these studies, which wereperformed only on indigenous populations, some cli-nicopathological features are repeatedly observed: theage of cancer presentation is a decade earlier than inEuropean or US patients, the average size of the lesionsis often greater than 20 mm, and the grade of tumors isoften higher. Interestingly, these data were corroboratedin our study of Arab/Moroccan immigrants. Indeed, inour series, the mean age of presentation of breast cancerwas 49 years old in Moroccan patients and occurred al-most a decade earlier than in European patients (meanage: 60 years old; p = 0.00001) (Table 1). These data aresimilar to those recently published by Chouchane et al.in a review article, in which the mean age of presenta-tion of breast cancer for Arab patients was 48 years old,compared to 63 years old in European women. Theseauthors also observed that two-thirds of the Arab pa-tients with breast cancer are younger than 50 years old[4]. We found similar results with our Arab immigrantpopulation. Indeed, 61% of the Arab patients with cancerwere less than 50 years old, compared to only 24% inthe European population (p = 0.0001) (Table 2). How-ever, these results should be interpreted with caution asthey may simply reflect that the immigrant population ison average younger than the European population andthat the Arab older patients have a different perceptionof breast cancer and therefore do not participate in thescreening program. These challenges and barriers tobreast cancer screening in Arab women have been dem-onstrated in several studies [17-19].The second observation on Arab patients frequently

found in the literature is the presence of larger tumors(mean tumor size greater than 20 mm) and a highergrade (grade 3) at diagnosis [20,21]. We were able toconfirm these findings in the general population used inour study. Indeed, over 50% of the Arab patients hadtumors larger than 20 mm, compared to 38% of theEuropean patients with a tumor greater or equal to 20 mm(p = 0.04). Furthermore, the average tumor size was 25 mm

asses in premenopausal women (in percentage).

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in the Arab patients, while it was only 19 mm in Europeans(p = 0.008) (Table 1). We also demonstrated that the Arabpatients had an increased incidence in grade 3 tumors (p =0.01) and fewer grade 1 tumors (p = 0.01) than Europeans.However, the data concerning the tumor size and

grade are only statistically significant in the general po-pulation, with all ages combined. Indeed, if we restrictour analysis to the premenopausal women under 50years old, the differences in the tumor size and grade areless obvious (Table 2). This phenomenon is consistentwith recent publications that establish a strong link be-tween age at diagnosis and the size and/or grade of thetumor [7,22]. Molecular subtyping of breast cancer geneexpression has resulted in a better understanding ofbreast carcinoma and several distinctive breast carcin-oma molecular subtypes have been identified [22,23]. Inaddition to this gene expression analysis, immunohisto-chemical surrogates have been used for breast cancerclassification with relatively good reproducibility [24]. Inthe present work, we demonstrated that the luminal sub-type B was the most common in an Arab/Moroccan im-migrant population. This subtype was found in 56% ofthe women in the general population but only in 40% ofthe European women (p = 002) (Table 1). In contrast,the luminal A subtype was significantly more commonin the European (46% than in the Arab patients (23%;p = 0.001). Interestingly, these statistically significant dif-ferences in the incidence of luminal A and B subtypes be-tween the two populations were also seen in patientsunder 50 years old (Table 2). However, no differences wereobserved for the subtypes HER2 and triple negative. Ourresults corroborate the study performed on a native popu-lation in Morocco, where the luminal B subtype was alsothe most common [6]. Deregulation in both genomic and/or proteomic expression of cytokeratin 8/18 and TFAP2C(a member of the AP-2 family) has been shown to regulateexpression of the ER, and the RET proto-oncogene mightcontribute to the high proportion of the luminal B subtypeobserved in Arab women. However, this observationshould be confirmed in future studies [25].

ConclusionsArab immigrant patients with breast carcinoma have dif-ferent clinicopathological features from those of Europeanwomen. In particular, the average age at presentation is al-most a decade earlier than in European women and ap-pears as a key factor that at least partially explains theother variable modifications, including the lesion size andhistological grade. Moreover, independent of age, the im-munohistochemical profile of the molecular classes is dif-ferent, with more luminal B and less luminal A subtypes,suggesting that there are clinicopathological differences,as well as disparities in the expression profiling in thesewomen.

AbbreviationsER: Estrogen receptor; PR: Progesterone receptor; HER2: Human epidermalgrowth factor receptor 2; FISH: Fluorescent in situ hybridization; CEP 17:Chromosome 17 centromere; TFAP2C: Transcription factor AP-2 gamma;AP-2: Activating protein 2; RET: Proto-oncogene tyrosine protein kinasereceptor.

Competing interestsThe authors declare that they have no competing interests.

Authors’ contributionsAll authors analyzed, interpreted, and approved the final manuscript.

FundingThis study has not received funding from a specific grant.

Received: 14 November 2013 Accepted: 21 December 2013Published: 4 February 2014

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doi:10.1186/1746-1596-9-26Cite this article as: Preat et al.: Differences in breast carcinomaimmunohistochemical subtypes between immigrant Arab and Europeanwomen. Diagnostic Pathology 2014 9:26.

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